P379: MUTATIONAL LANDSCAPE IN THERAPY-RELATED ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: K. D. Hofer, E. Haralambieva, C. Fritz, M. Roncador, C. Ruetsche, M. Buehler, J. Tchinda, U. Schanz, C. C. Widmer
Journal: HemaSphere (2022)

Background: There is increasing evidence that therapy-related acute lymphoblastic leukemia (t-ALL) with a reported incidence of 3% to 9% is a distinct entity, which is associated with inferior survival compared with de novo ALL (dn-ALL). It appears that this results from a poor cytogenetic predisposition, but data are still very limited due to the rarity of the disease and the mutational landscape has not been adequately explored, as molecular analyses are sparse in this unique patient cohort. Aims: This study attempted to investigate the molecular landscape of patients with an initial diagnosis of ALL and a prior history of malignancy with consecutive genotoxic therapy and to evaluate the cytogenomic results and survival. Methods: Data were collected from 131 adult patients with an initial diagnosis of ALL treated at the Department of Medical Oncology and Hematology, University Hospital Zurich, Switzerland. Patients with prior treatment of another malignancy with alkylating agents, topoisomerase inhibitors, radioactive iodine ablation (for thyroid cancer) and/or irradiation were classified as t-ALL. Results: Within our ALL cohort, 14% of the patients met the criteria for t-ALL. The median latency between genotoxic therapy and diagnosis of t-ALL was 6.5 years, with breast cancer being the most common neoplasm. KTM2A rearrangement was not significantly more common in t-ALL than in dn-ALL (15.7% vs 11%, p = 0.15), a finding which was not as expected from the literature. In therapy-related myeloid neoplasms large chromosomal deletions, such as del(5q) and del(7q) are known to be associated with alkylating agents and topoisomerase II inhibitors. In 12% of our t-ALL patients deletions in chromosome 7 were found, but none in chromosome 5. On the other hand, a high proportion of Philadelphia chromosome (Ph) 36.8% was present in the t-ALL group. On a molecular level, the most frequently observed mutation was KMT2D, followed by myeloid neoplasm-associated mutations of CDKN2A, KRAS and DNTM3A, but no TP53 mutation was found. KRAS mutation was never present in combination with Ph+, but was associated with KMT2A rearrangement. Outcome was particularly poor in Ph+ t-ALL patients compared to Ph+ dn-ALL, an effect that was mitigated by allogeneic stem cell transplantation. Image:Summary/Conclusion: In addition to KMT2A rearrangement as a high-risk genomic subtype, a high proportion of Ph+ was observed in the t-ALL group. Ph+ t-ALL showed a different mutational landscape than KTM2A-mutated patients, suggesting that the development of t-ALL is driven by multiple pathways with particularly bad outcome for patients with Ph+. Although there is overlap in the molecular profile of t-ALL and myeloid neoplasms, no TP53 mutation was found in our t-ALL cohort. The heterogeneity of the genetic aberrations in ALL render molecular genome sequencing of somatic variants an important step to advance our understanding of the disease, especially in those patients without KTM2A rearrangement but Ph positivity. Our findings help further define therapy-associated ALL as a distinct entity, but also highlight the need for a better molecular understanding of its specific disease evolution.